Use of phy906 as treatment for inflammatory bowel disease and/or irritable bowel syndrome

ABSTRACT

The present invention includes a method of using PHY906 for treating a bowel disorder including inflammatory bowel disease and irritable bowel syndrome. Particularly, the present invention provides a multiple symptoms treatment for the bowel disorder.

RELATED PATENT AND APPLICATIONS

This application claims benefit to U.S. Provisional Patent ApplicationNo. 60/982,608, filed on Oct. 25, 2007 and entitled “Use of PHY906 asTreatment for Inflammatory Bowel Disease and/or Irritable BowelSyndrome”, which is herein incorporated by reference in its entirety.

This application is related to U.S. patent application Ser. No.09/522,055, entitled “Herbal Composition PHY-906 and Its Use inChemotherapy”, which was filed on Mar. 9, 2000 and abandoned;International Application PCT/US01/07353, entitled “Herbal CompositionPHY906 and Its Use in Chemotherapy”, which was filed Mar. 8, 2001 andpublished as WO 2001/66123; U.S. Provisional Patent Application No.60/625,943 filed on Nov. 9, 2004 and entitled “Herbal CompositionPHY-906 and Its Use in Chemotherapy”; U.S. patent application Ser. No.11/100,433, entitled “Herbal Composition PHY906 and Its Use inChemotherapy”, which was filed on Apr. 7, 2005 and published as U.S.2005/0196473A1; International Application PCT/US05/40605, filed on Nov.9, 2005 and published as WO 2006/53049; and U.S. Pat. No. 7,025,993,entitled “Herbal Composition PHY906 and Its Use in Chemotherapy”, whichwas issued on Apr. 11, 2006; all of which are herein incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the use of PHY906 for treating a boweldisorder, such as, for example, inflammatory bowel disease (IBD) andirritable bowel syndrome (IBS).

BACKGROUND OF THE INVENTION 1. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) encompasses a group of conditions thatexhibit inflammation of the large and, in some cases, small intestine.The two main forms of IBD are Crohn's disease and ulcerative colitis(UC). Other much less common manifestations of IBD are collagenouscolitis, lymphocytic colitis, ischaemic colitis, diversion colitis,Behçet's syndrome, infective colitis, and indeterminate colitis.Diagnosis is generally by colonoscopy with biopsy of pathologicallesions.

In the US, in 2001, the prevalence of Crohn's disease and UC was 162 and246 cases per 100,000, respectively⁽¹⁾. Although the mortality rate fromIBD is low, hospitalizations for 2002 totaled 169,000 (62% for Crohn'sdisease) and ambulatory care visits approximated 5.9 million per year in1999-2000^((2,3)). In the early 1990s, over 160,000 people in the USwith IBD were considered disabled⁽⁴⁾.

The majority of Crohn's cases start in the terminal ileum, but it canaffect any part of the gastrointestinal tract. In contrast, UC isrestricted to the colon. From a microscopic point of view, whereasCrohn's disease affects the entire bowel wall, UC is restricted to theepithelial lining of the gut. Both UC and Crohn's show extra-intestinalmanifestations, e.g. liver problems, arthritis, eye problems, skinmanifestations, they are present in different proportions in eachdisease.

Most medical treatment for IBD is aimed at controlling the ongoinginflammation and is directed to achieving and maintaining remission.Since the symptoms, course of disease, and prognosis vary from patientto patient, no standard treatment exists for IBD. An accurate diagnosis,usually achieved through the use of endoscopic, radiological, andpathologic examinations, is imperative for designing a proper course oftreatment. Currently, for IBD, the five main classes of medications usedare: aminosalicylates, corticosteroids, immunomodulators, antibiotics,and biologics⁽⁵⁾.

Aminosalicylates:

Aminosalicylates are effective in treating mild to moderate cases of IBDas well as preventing relapses and maintaining remission. They areusually administered orally or rectally. Sulfasalazine (Azulfidine®),the first aminosalicylate to be widely used for IBD, is effective inachieving and maintaining remission in people with mild-to-moderatedisease. It delivers 5-aminosalicylic acid (5-ASA) to the intestine butcomes with disagreeable side effects in some patients, such as headache,nausea, loss of appetite, vomiting, rash, fever, and decreased whiteblood cell count. Sulfasalazine can decrease sperm production andfunction in men while they are taking the medication. It has beenassociated with pancreatitis in rare cases. The headaches, nausea, andrash are thought to be due to the release of the sulfapyridine moietythat is necessary for delivery of the 5-ASA to the intestine.

Other derivates of 5-ASA have also been synthesized. Those derivativesinclude mesalamine (Asacol®, Pentasa®), olsalazine (Dipentum®), andbalsalazide (Colazal™). Local mesalamine preparations bypass the stomachto avoid early digestion, and then release close to the inflamed sectionof the bowel. Oral, delayed-release preparations such as Pentasa® andAsacol® can release 5-ASA directly to the small intestine and colon, orto the ileum and/or colon, respectively. Rowasa®, an enema formulationof mesalamine, allows the drug to be applied directly to the left colon.Rowasa® is effective in 80% of patients with mild-to-moderate colitisthat affects only the left side of the colon. Mesalamine suppositories(Canasa®) that deliver the drug directly from the rectum up to thesigmoid colon are effective in a high proportion of patients with UClimited to the rectum and the lower end of the colon. Dipentum®, anoral, delayed-release preparation of olsalazine, delivers 5-ASA directlyto the colon only.

Corticosteroids:

As fast-acting anti-inflammatory and immunosuppressive agents,corticosteroids have been used for treating acute flare-ups of IBD forover 50 years. Since that time, these powerful agents have been themainstay of treatment for disease. Most patients notice an improvementin symptoms within days of starting corticosteroids⁽⁶⁾. This group ofmedications is available in oral, rectal, and intravenous (IV) forms.Corticosteroids are not effective in preventing flare-ups and thereforeare rarely used for maintenance therapy in IBD. Since long-term useresults in side effects, these agents are recommended only forshort-term use in order to achieve remission, but they are not usedfrequently in the latter case. For people with moderate to severe activedisease, oral corticosteroids include prednisone (Deltasone®),methylprednisolone (Medrol®), and hydrocortisone. Aminosalicylates areoften taken together with corticosteroids.

Budesonide (Entocort®), an oral corticosteroid, is used to treatmild-to-moderate Crohn's disease involving the end of the smallintestine and/or the first part of the large intestine. This nonsystemicsteroid targets the intestine rather than the whole body.Corticosteroids may also be given rectally as enemas (hydrocortisone,methylprednisone, Cortenema®), foams (hydrocortisone acetate,ProctoFoam-HC®), and suppositories. Such preparations are used formild-to-moderate ulcerative colitis that is limited to the rectum orlower part of the colon. When used in combination with other therapies,these agents are also effective against more widespread disease thatstarts at the rectum. Methylprednisone and hydrocortisone are oftengiven by IV infusion to patients with severe and extensive disease.Acute IBD does not respond to corticosteroid therapy in 20-30% of casesand in 30-40% of cases with moderate to severe disease, corticosteroidscannot be abruptly discontinued without occurrence of a diseaseflare-up.

Immunomodulators:

Since IBD appears to be caused by an overactive immune system,immunomodulators play an important role in the treatment of thisdisease⁽⁷⁾. These drugs are used for those who have one of the followingcharacteristics: (a) side effects with corticosteroid treatment, (b)steroid-dependent disease, (c) do not respond to aminosalicylates,antibiotics, or corticosteroids, (d) perineal disease that does notrespond to antibiotics, and (e) need to maintain remission. These drugsmay be combined with a corticosteroid to speed up response during activeflares of disease.

Azathioprine (Imuran®, Azasan®) and 6-mercaptopurine (6-MP, Purinethol®)are oral immunomodulators that are used to maintain remission in Crohn'sdisease and UC. Since these agents have a slow onset of action, they areusually given along with another faster-acting drugs, e.g.corticosteroids. Other immunomodulators used for IBD are cyclosporine A(Sandimmune®, Neoral®) and tacrolimus (Prografe®). Of these agents,cyclosporine A has the fastest onset of action. When given IV at highdoses, cyclosporine A is useful against active Crohn's disease. Thisdrug is effective against severe UC as is tacrolimus. The latter agentcan be used against Crohn's when corticosteroids are not effective orwhen fistulas develop. Tacrolimus may be applied topically to treatCrohn's disease of the mouth or perineal area. An option for people withCrohn's disease who do not respond to other treatments and cannottolerate other immunosuppressants is IV-administered Methotrexate (MTX,Rheumatrex®, Mexate®).

Antibiotics:

Although no specific infectious agent has been identified as the causeof IBD, antibiotics are frequently used as a primary treatment⁽⁸⁾.Antibiotics are effective as long-term therapy in Crohn's diseasepatients who have fistulas (between loops of intestine or betweenintestine and adjacent organs, e.g. skin) or recurrent abscesses nearthe anus. Patients whose active disease is successfully treated withantibiotics may be kept on these as maintenance therapy. Generally,antibiotics are not considered useful for those with UC; the exceptionis toxic megacolon.

The most frequently prescribed broad-spectrum antibiotics for IBD aremetronidazole (Flagyl®) and ciprofloxacin (Cipro®). Metronidazole is aprimary therapy for active Crohn's and has been shown to reduce therecurrence of Crohn's for the first three months after ileum resectionsurgery. This drug is effective in managing perineal Crohn's in over 50%of cases. Ciprofloxacin, much safer than metronidazole, is commonly usedto treat active Crohn's disease. Both oral and IV metronidazole andciprofloxacin are used for IBD treatment.

Biologics:

Possible targets by which biologics may interfere with the body'sinflammatory response in IBD include tumor necrosis factor-alpha(TNF-α), interleukins, adhesion molecules, colony-stimulating factors,and others⁽⁹⁾. Since their mechanism is targeted, biologic therapiesoffer a distinct advantage in IBD treatment. Unlike corticosteroids,which tend to suppress the entire immune system and thereby producemajor side effects, biologic agents act selectively. Biologics aretargeted to particular enzymes and proteins that have already beenproven defective, deficient, or excessive in people with IBD or inanimal models of colitis.

Anti-TNF agents have been used in both Crohn's disease and UC. Thechimeric monoclonal antibody Infliximab (Remicade®) is approved forCrohn's disease and fistulizing Crohn's disease, as well as for UC.Given as an IV drip, it is used for people with moderately-to-severelyactive disease who have not responded well to other therapies.Adalimumab (Humira®), a fully human monoclonal antibody given byinjection, is used for people with moderately to severely active Crohn'sdisease who have not responded well to other therapies and who have lostresponse or are unable to tolerate infliximab. Certolizumab pegol(currently known as Cimzia™), is currently being investigated for use inCrohn's disease.

Adhesion molecule inhibitors are being evaluated as IBD therapies. Thesedrugs work by binding to particular cells in the bloodstream that arekey players in inflammation. Natalizumab (Tysabri®), already approvedfor multiple sclerosis, is an adhesion molecule inhibitor currentlyunder investigation for the treatment of Crohn's disease.

Visilizumab (Nuvion®), a humanized monoclonal antibody directed againstCD3 receptors on activated T cells, and alicaforsen, a drug thatinhibits ICAM-1 (plays a key role in intestinal inflammation) areCurrently being investigated as possible treatments for UC. Otherpotential IBD agents include thalidomide, the interleukins IL-6, IL-10,IL-11, and IL-12, interferon gamma, and granulocyte-macrophagecolony-stimulating factor (GM-CSF).

Surgery:

In spite of the above medication options for IBD, 66-75% of Crohn'spatients and 25-40% of those with UC will eventually undergosurgery^((10, 11)). Surgery for Crohn's disease depends upon thelocation of the disease. If it is in the small intestine, areas ofdiseased bowel may alternate with areas of normal bowel. The areas ofactive disease may narrow, forming strictures, which can block thepassage of digested food. If the lesions are separated, strictureplastyis often used. Here, the strictured areas are widened and the smallintestine is spared. Resection and anastimosis may be needed if thestricture is long or if there are multiple strictures close to eachother. Although resection may offer years of relief, disease can recurat or near the site of the anastimosis. In patients with severe Crohn'sin the colon, colectomy may be done. If the rectum is unaffected the endof the ileum may be rejoined to the rectum; thus, stool may be passednormally. If both the colon and rectum are involved, proctocolectomywith subsequent ileostomy may be performed. Fistulas and/or abscesseseventually develop in about 25% of patients with Crohn's disease. Iffistulas are unresponsive to medication, they are removed by resectionof the affected bowel followed by anastimosis. Abscesses must bedrained; in some cases, this requires resection. For years, the standardsurgery for UC has been proctocolectomy with ileostomy. Now the mostcommon procedure is restorative proctocolectomy; this allows the patientto continue to pass stool through the anus. Unlike Crohn's disease,which can recur after surgery, UC is “cured” once the colon is removed.

2. Irritable Bowel Syndrome

Irritable bowel syndrome (IBS, spastic colon) is a functional boweldisorder characterized by abdominal pain and changes in bowel habits.Unlike IBD, IBS is not associated with abnormalities seen on clinicaltesting. The most frequent symptoms of IBS are the lower abdominal painand bloating associated with alteration of bowel habits, and abdominaldiscomfort relieved by defecation. IBS is may be classified asdiarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or withalternating stool pattern (IBS-A). Sometimes, IBS may have an acuteonset and develop after an infectious illness characterized by two ormore of the following symptoms: fever, vomiting, acute diarrhea, andpositive stool culture; this form, which has been termed post-infectiveIBS (IBS-PI), consists mostly of IBS-D.

Approximately 20 percent of people in the US have symptoms of IBS andthese symptoms occur before the age of 35 in about 50 percent ofcases⁽¹²⁾. About one-third of all patients suffer from IBS-D. Althoughmortality from IBS is very low, hospitalizations in 2002 totaled190,000, ambulatory care visits totaled 1.3 million per year in1999-2000, and 46,000 patients with IBS were deemed disabled in1990-1992⁽²⁻⁴⁾. In 1985, 2.2 million prescriptions per year were writtenfor IBS⁽¹³⁾. IBS in general and IBS-D in particular have a significantnegative impact on the quality of life (QOL) for the many people whosuffer from this condition; it causes lost days from work and interferessignificantly with home-based, social, and leisure activities.

IBS treatment involves reassuring patients that their disease is notlife-threatening, giving dietary advice, and prescribing medication.Immune response to some foods may play a role in the reduction orelimination of IBS symptoms in some cases^((14, 15)). IBS patients aresensitive to fats, insoluble fibers, caffeine, carbonation, alcohol,fructose, foods with elevated levels of IgG4 antibodies, and foods thatmay increase colonic contractions⁽¹⁵⁻²⁰⁾.

For IBS-C patients, medications include stool softeners and laxatives.For IBS-D sufferers, medications consist of antidiarrheals, e.g. opiodsor opiod analogs (loperamide, Imodium®; diphenoxylate; diphenoxylateplus atropine, Lomotil®). Severe cases may be treated with codeine orpropoxyphene (Darvon®) and refractory cases may be treated withparegoric or even morphine. Low doses of tricyclic and selectiveserotonin reuptake inhibitory antidepressants are widely prescribed forthe relief of pain and diahhrea, respectively. Alosetron (Lotronex®), aselective 5-HT3 antagonist is available for women in the US who haveIBS-D only. Cilansetron (Calmactin®), another selective 5-HT3antagonist, is currently in clinical trials in Europe for the treatmentof IBS-D in both men and women. In 2005, the sponsor of cilansetronwithdrew its application for approval from the US FDA on the basis of a“non-approvable” letter (additional clinical trials were requested).Tegaserod (Zelnorme®), a selective 5-HT4 antagonist for IBS-C, is theonly agent approved to treat constipation, abdominal pain, and bloatingin women in the US; it is not approved in the EU, however. The potentialrole of bacterial overgrowth in some patients with IBS is suggested byrecent studies suggesting that rifaximin is an effective treatment forabdominal bloating and flatulence^((21,22)).

Alternative treatments for IBS include probiotics (potentiallybeneficial strains of bacteria and yeast found in the human gut, e.g.Lactobacillus planarium LP299V and Bifidobacterium infantis35625)^((23,24)). Clinical studies with probiotics are currently beingconducted in the US⁽²⁵⁻²⁹⁾.

3. Traditional Chinese Medicine for Treating Bowel Disorders

Mixtures of botanical extracts have been widely used throughout theworld for the management of disease and are gaining increased acceptancein Western countries⁽³⁵⁻³⁸⁾. The use of herbal Traditional ChineseMedicine (TCM) is based on many chemical components in an herbalpreparation that interact and act simultaneously through multiplemolecular targets and cellular mechanisms. These multiple componentsserve various functions; some may be responsible for efficacy whileothers may decrease toxicity or increase bioavailability. Chinese herbalformulations are perhaps the best-known botanical medicines to have beenderived from empirical observations in humans over the millennia. Theclaimed indication of a given Chinese medicinal preparation is multiplerather than single. This is not surprising; many phytochemicalingredients in a formulation can exert actions at multiple targets andbiological pathways.

Aspects of Traditional Chinese Medicine (TCM), including acupuncture andherbal medicines, have also been examined as possible IBS treatments.The benefits of acupuncture for the treatment of IBS have not beenproven conclusively⁽³⁰⁾. Many studies were not of adequate size and/orwere uncontrolled or poorly controlled. In a well-controlled study of 43IBS patients where the efficacy of acupuncture following the rules ofTCM was compared with that of sham (placebo) acupuncture, aninsignificant difference was seen'between the two groups⁽³¹⁾. Twoclinical studies on the effects of acupuncture on IBS have recently beencompleted in the US, but the results have not yet been published⁽³²⁾.

Several clinical studies in China have suggested the potential of TCMherbal formulations in the treatment of IBS, but these have lackedadequate trial design, poor randomization techniques, and/or lack ofblinding⁽³³⁾. In a randomized, placebo-controlled trial where 116patients were treated with placebo, with a “standard” formulation of 20herbs, or with “individualized” herbal formulations, patients treatedwith the herbal formulations had more symptom improvement than placebocontrols⁽³³⁾. In contrast, in a randomized double-blindedplacebo-controlled trial involving 119 patients with IBS-D treated witheither placebo or an eleven-herb TCM formulation, no significantdifference was seen between the two arms in terms of global symptomimprovement⁽³⁴⁾.

In summary, IBD and IBS are common chronic illnesses with multiplesymptoms that can be very serious and debilitating. Numerous treatmentsfor IBD and IBS have been developed, but most of these treatments do nothave desirable efficacy or are single-symptom remedies.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a method of treating abowel disorder comprising administering to a patient in need thereof atherapeutically effective amount of a composition comprising an herbalpreparation having Scutellaria, Glycyrrhiza, Ziziphus and Paeonia.

In another embodiment, the present invention provides a method ofinhibiting a 5-opioid receptor or a tachykinin NK-1 receptor bycontacting the 8-opioid and tachykinin NK-1 receptors with a compositioncomprising an herbal preparation having Scutellaria, Glycyrrhiza,Ziziphus and Paeonia.

In another embodiment, the present invention provides a method ofinhibiting a nuclear factor-kappa B (NF-κB) by contacting the NF-κB witha composition comprising an herbal preparation having Scutellaria,Glycyrrhiza, Ziziphus and Paeonia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph showing the change of initial tumor size aftervarious days of CPT-11 treatment and thereby demonstrating the antitumorefficacy of the combination of PHY906 and CPT-11. Methods: A singlebolus dose (360 mg/kg) of CPT-11 was administered to BDF-1 mice bearingmurine Colon 38 tumors on day 0, 30 min after PHY906 (500 mg/kg). PHY906administration was continued bid for 4 days. Treatment groups consistedof 5 mice each. FIG. 1A shows antitumor effects. Vertical linesindicate + (up) or − (down) one standard derivation (SD).

FIG. 1B is a graph showing the change of body weight after various daysof CPT-11 treatment and thereby demonstrating the reduction of CPT-11toxicity by PHY906. Methods: A single bolus dose (360 mg/kg) of CPT-11was administered to BDF-1 mice bearing murine Colon 38 tumors on day 0,30 min after PHY906 (500 mg/kg). PHY906 administration was continued bidfor 4 days. Treatment groups consisted of 5 mice each. FIG. 1B showsbody weights. Vertical lines indicate + (up) or − (down) one standardderivation (SD).

FIG. 2 is a Kaplan-Meyer survival curve demonstrating the reduction oftoxicity CPT-11 toxicity by PHY906. Methods: A single bolus dose (360mg/kg) of CPT-11 was administered to BDF-1 mice bearing murine Colon 38tumors on day 0, 30 min after PHY906 (500 mg/kg). PHY906 administrationwas continued bid for 4 days. Treatment groups consisted of 5 mice each.

FIG. 3 is a graph demonstrating the inhibitory effect of PHY906 againstboth intrinsic and TNF-induced NF-κB.

DETAILED DESCRIPTION OF THE INVENTION

During a literature search of Chinese medicinal formulations that havebeen used to treat symptoms similar to those that are associated withmodern cancer chemotherapy, PHY906 was selected from among the severalformulations found. PHY906, a decoction of a mixture of four herbs, wasestablished more than 1500 years ago for the treatment of diarrhea,abdominal spasms, fever, headache, vomiting, nausea, extreme thirst, andsubcardial distention⁽³⁹⁾.

PHY906 includes at least four herbs commonly known as Scute, Licorice,Peony Alba and Ziziphi Fruit (Table 3). Thus, one plant species ischosen from each one of the four plant groups provided in Table 3 inorder to produce the desired herbal compositions of the presentinvention. While particular combinations of the listed plant species areprovided as examples of preferred PHY906 formulations, the compositionsand methods of this invention encompass any combination of four plantspecies wherein a plant species is selected from each one of the fourgroups in Table 3. This invention encompasses any such combination ofsuch herbs which have at least one of the biological activities ordesired effects ascribed to PHY906 as described herein.

TABLE 1 Examples of Particular Species of Four Genera which can be Usedto make PHY906. Common English Name of TCM Herbal Group ScutellariaLicorice Peony Alba Ziziphi Fruit Anemone rivularis Abrus mollis HancePaeonia delavayi Ziziphusjujuba Mill. Buch.-Ham. ex DC. Franch. var.lutea (Delavay ex Mill. Franch.) Finet et Gagnep. Thalictrum omelenseGlycyrrhiza aspera Paeonia lactiflora Ziziphusjujuba Mill. W. T. Wang etS. H. Wang Pall. Pall. var. inermis Mahonia bealei (Fort.) Glycyrrhizaeurycarpa Paeonia mairei Levi. Carr. P. C. Li Nandina domesticaGlycyrrhiza glabra L. Paeonia obovata Thunb. Maxim. var. willmottiae(Stapi) Stern Scutellaria amoena Glycyrrhiza inflata Daphne papyracea C.H. Wright Bat. Wall. ex Steud. Scutellaria amoena Glycyrrhiza CynanchumC. H. Wright var. squamulosa Franch. otophyllum Schneid. cinereaHand.-Mazz. Onuma Scutellaria baicalensis Glycyrrhiza uralensisCodonopsis Georgi Fisch. lanceolara Sieb. et Zucc. Trautv. Scutellariabaicalensis Phlomis betonicoides Georgi var. albiflora K. DielsScutellaria hypericifolia Levl Scutellaria likiangensia DielsScutellaria obtusifolia Hemsl. var. trinervata (Vant.) C. Y. Wu et H. W.Li Scutellaria regeliana Nakai Scutellaria regeliana Nakai var.ikonnikovii (Juz.) C. Y. Wu et H. W. Li Scutellaria ehderiana DielsScutellaria Licorice Peony Alba Ziziphi Fruit Scutellaria tenax W. W.Smith var. patentipilosa (Hand.- Marz.) C. Y. Wu Scutellaria viscidulaBunge

In one embodiment, PHY906 includes Scutellaria baicalensis Georgi (scutebaical skullcap root), Paeonia lactiflora Pall. (white peony root),Glycyrrhiza uralensis Fisch. (licorice root), and Ziziphus jujube Mill.(date fruit); which are mixed in a ratio of 1.5:1:1:1 by weight,respectively. Each of the four herbs of PHY906 is reported to possess adistinct pharmacological profile; these include anticancer and antiviralactivity, hematological and immunological stimulation, analgesicactivity, liver protection, and appetite improvement⁽⁴⁰⁾. An alternativeformulation of PHY906 has the herbs Scutellaria, Glycyrrhiza, Ziziphus,and Paeonia in the following relative proportions: 4/14:3/14:4/14:3/14,respectively.

While specific ratios of the herbs of PHY906 are provided as examples,the compositions and methods of this invention encompass any ratios ofthe four herbal components which have the desired biological activity asdescribed herein.

In one embodiment, PHY906 can be produced by a process as describedhereinbelow. First, the proper ratios of the ingredients of the herbalraw materials are placed in a jacketed reactor and extracted with waterat an elevated constant temperature with mixing. The ratios are setforth in the Manufacturing Instruction reproduced from Master FormulaRecord. The solid materials are then separated from the liquid with a120-mesh screen. The filtrate is collected and then concentrated byevaporating the water under reduced pressure. The concentrated liquor isspray dried at an elevated temperature to yield dry powder which is thenprocessed to yield granulated powder. This bulk substance is thenformulated into the desired dosage form.

Process controls are utilized to ensure the uniformity and integrity ofthe product. Such process controls include, but are not limited to,checking the volume of the process liquor, HPLC determinations toestablish Chemical Fingerprintings to verify identity of the rawmaterials, and inspections and tests of intermediate and final products.Accepted Quality Level (AQL) Limits are established for each conductedanalysis and for each step of the manufacturing and control ofproduction. All of the components used in the production process areassigned a specific lot number in the Production Instruction Record.Quality control records are reviewed before a batch is released.Purified marker substances are used for identification and qualitycontrol of the raw materials as well as the herbal substances. Table 2lists the marker substances of each raw material used in the preparationof PHY906 herbal substance.

TABLE 2 Marker Substances for Herbal Ingredients of PHY906 Origin ofHerb Marker Herb Producing Place Substance Scutellaria baicalensis ShangXi Province, China Baicalin Georgi. Glycyrrhiza uralensis Fisch: InnerMongolia, China Glycyrrhizin Ziziphus jujuba Mill. Hebei/ShangtongChelidonic Province, China Acid Paeonia lactiflora Pall. An HweiProvince, China Paeoniflorin

The compositions of the present invention can be administered viaparenteral, subcutaneous, intravenous, intramuscular, intraperitoneal,transdermal, or buccal routes. Alternatively, or concurrently,administration may be by the oral route. The dosage administered will bedependent upon the age, health, and weight of the recipient, the type ofconcurrent treatment, if any, the frequency of treatment, and the natureof the effect desired.

The pharmaceutical formulation for systemic administration according tothe invention may be formulated for enteral, parenteral, or topicaladministration. Indeed, all three types of formulations may be usedsimultaneously to achieve systemic administration of the activeingredient. While individual needs vary, determination of optimal rangesof effective amounts of each component is within the skill of the art.

In addition to the pharmacologically active agent, the compositions ofthe present invention may contain suitable pharmaceutically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically for delivery to the site of action.

PHY906 can be used in the form of a medicinal preparation, for example,in solid, semi-solid or liquid form which contains PHY906, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for external, enteral, or parenteral applications.The active ingredient may be compounded, for example, with the usualnon-toxic pharmaceutically acceptable carriers for tablets, pellets,capsules, suppositories, solutions, emulsions, suspensions, and anyother form suitable for use.

Formulations of the present invention encompass those which includetalc, water, glucose, lactose, gum acacia, gelatin, mannitol, starchpaste, magnesium trisilicate, corn starch, keratin, colloidal silica,potato starch, urea, and other carriers suitable for use inmanufacturing preparations, in solid, semisolid or liquid form and inaddition auxiliary, stabilizing, thickening and coloring agents, andperfumes may be used.

For preparing solid compositions such as tablets or capsules, PHY906 ismixed with a pharmaceutical carrier (e.g., conventional tabletingingredients such as corn starch, lactose, sucrose, sorbitol, talc,stearic acid, magnesium stearate, dicalcium phosphate or gums) and otherpharmaceutical diluents (e.g., water) to form a solid preformulationcomposition containing a substantially homogeneous mixture of PHY906, ora non-toxic pharmaceutically acceptable salt thereof. When referring tothe preformulation compositions as substantially homogenous, it is meantthat the active ingredients are dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.

This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing an effective amountof the composition of the present invention, preferably in capsules.

The tablets or pills containing PHY906 can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms, in which PHY906 may be incorporated for administrationorally or by injection, include aqueous solution, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil, or peanut oil aswell as elixirs and similar pharmaceutical vehicles. Suitable dispersingor suspending agents for aqueous suspensions include synthetic naturalgums, such as tragacanth, acacia, alginate, dextran, sodiumcarboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone orgelatin.

Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for reconstitution with water or other suitable vehiclesbefore use. Such liquid preparations may be prepared by conventionalmeans with pharmaceutically acceptable additives such as suspendingagents (e.g., sorbitol syrup, methyl cellulose or hydrogenated ediblefats); emulsifying agents (e.g., lecithin or acacia); non-aqueousvehicles (e.g., almond oil, oily esters or ethyl alcohol); preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid); andartificial or natural colors and/or sweeteners.

For buccal administration, the compositions of the present invention maytake the form of tablets or lozenges formulated in conventional manners.

PHY906 may also be formulated for parenteral administration byinjection, which includes using conventional catheterization techniquesor infusion. Formulations for injection may be presented in unit dosageform, e.g., in ampules, or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulating agents such as suspending, stabilizing, and/or dispersingagents. Alternatively, the active ingredients may be in powder form forreconstitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts. In addition, suspensions of the active compounds asappropriate oily injection suspensions may be administered. Suitablelipophilic solvents or vehicles include fatty oils, for example, sesameoil, or synthetic fatty acid esters, for example, ethyl oleate ortriglycerides. Aqueous injection suspensions may contain substanceswhich increase the viscosity of the suspension include, for example,sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally,the suspension may also contain stabilizers.

Liposomes can also be used to encapsulate the agent for delivery intothe cell.

In practicing the methods of this invention, PHY906 may be used alone orin combination, or in combination with other therapeutic or diagnosticagents. In certain preferred embodiments, the compounds of thisinvention may be coadministered along with other compounds typicallyprescribed for cancer chemotherapy according to generally acceptedmedical practice. The compounds of this invention can be utilized invivo, ordinarily in mammals, such as humans, sheep, horses, cattle,pigs, dogs, cats, rats and mice, or in vitro.

Actual methods for preparing administrable compositions and adjustmentsnecessary for administration to subjects will be known or apparent tothose skilled in the art and are described in more detail in, forexample, Remington's Pharmaceutical Science, 17th Ed., Mack PublishingCompany, Easton, Pa. (1985), which is incorporated herein by reference.

PHY906 has proven to be efficacious in enhancing the therapeutic indicesof a variety of anticancer agents including CPT-11 (irinotecan,Camptosar®). CPT-11 is a water-soluble derivative of camptothecin (anantitumor alkaloid isolated from Camptotheca acuminata) that exhibits awide spectrum of antitumor activity because of its inhibition of DNAtopoisomerase I⁽⁴¹⁾. CPT-11 is a component of some of the most widelyused chemotherapy treatment regimens (e.g. the “Saltz” regimen [CPT-11plus 5-fluorouracil/leucovorin], IFL, FOLFIRI, AIO) for colorectalcancer^((42,43)). Diarrhea has long been recognized as one of the mostcommon limiting side effects associated with CPT-11 use, regardless ofthe schedule of administration⁽⁴⁴⁻⁴⁶⁾. It causes two types of diarrhea:(a) early acute diarrhea that occurs soon after CPT-11 administrationand (b) late-onset diarrhea that occurs usually after an average periodof 6 days. In about 40% of patients, this side effect is classifiedgrade 3 (serious) or grade 4 (life-threatening) according to theNational Cancer Institute Common Toxicity criteria⁽⁴⁷⁾. High-doseloperamide is considered standard treatment for CPT-11-induced diarrheain Europe and the US, but the success of this approach is limited⁽⁴⁸⁾.

CPT-11 is hydrolysed by hepatic carboxylesterase to its active (as ananticancer agent) metabolite, SN-38⁽⁴⁹⁾. This metabolite can then beconjugated to SN-38 glucuronide (SN-38G, an inactive metabolite) byUDP-glucuronyltransferase⁽⁵⁰⁾. CPT-11, SN-38, and SN-38G are excretedinto the bile⁽⁵⁰⁾. Once in the intestine, SN-38G can be deconjugated toSN-38 by bacterial β-glucuronidase in the cecum and colon⁽⁵¹⁾. SN-38 isbelieved to be responsible for CPT-11 treatment-related diarrhea⁽⁵²⁾.

In preclinical studies; when PHY906 was used in combination with CPT-11in mice bearing Colon 38 tumors, the antitumor efficacy of thecombination was greater than that of CPT-11 alone (FIG. 1A), and thetoxicity (as measured by body weight loss and mortality) seen withPHY906+CPT-11 was reduced over that seen with CPT-11 alone (FIG.1B)⁽⁵³⁾. The reduced toxicity of the combination is also shown byKaplan-Meyer survival curves (FIG. 2) that depict the reduced mortalityof the combination vs. CPT-11 alone. Although the effects of PHY906 onCPT-induced diarrhea were not directly measured, the reduction by PHY906of body weight loss induced by CPT-11 acts as a “surrogate” marker fordiarrhea reduction. In mice bearing Colon 38 tumors and treated with ahigh dose of CPT-11, PHY906 proved to be much more effective in reducingbody weight loss than other “antidiarrheals” including loperamide andthe Chinese herbal formulations TJ-14ST, TJ-15, and PHY915⁽⁵⁴⁾.

The reduction in CPT-11-induced diarrhea by PHY906 may be due to itspotent inhibition of bacterial β-glucuronidase (deconjugates SN-38G toSN-38, the toxic form of CPT-11)⁽⁵⁴⁾. Baicalein, found in Scutellariabaicalensis Georgi (one of the constituent herbs of PHY906) is afeedback inhibitor of β-glucuronidase⁽⁵⁵⁾. In addition, PHY906 containscompounds that are alternative substrates for β-glucuronidase; thesecould compete with SN-38G for binding to the enzyme.

On the basis of the above and other preclinical studies, an FDA-approvedPhase I/IIa multicentered and randomized double-blind placebo-controlledsafety study with cross-over dose escalation was launched in 2002 inpatients with advanced, refractory colorectal cancer. In the study, thecombination of CPT-11 plus 5-fluorouracil/leucovorin (5-FU/LV)supplemented by PHY906 or placebo was used as first-line treatment.PHY906 was shown to be safe with no serious adverse events (SAEs)attributed to the study drug. PHY906 was found to have no appreciableeffect on the metabolism of CPT-II or 5-FU in controlled metabolictesting (pharmacokinetic study). Fifteen of seventeen patients treatedshowed either a partial response or stable disease after two courses oftreatment. Reduction of diarrhea/nausea/vomiting induced by CPT-11treatment was observed in the cross-over, internal, patient controls.PHY906 reduced the amount of loperamide necessary to treatCPT-11-induced diarrhea. At a dose of 1.2 g/day, PHY906 reduced theseverity of diarrhea by one grade and, at a dose of 2.4 g/day, itreduced nausea/vomiting by one grade^((56,57)).

In one embodiment, the present invention provides a method of relievingside effects of a chemotherapeutic compound in a patient in need thereofcomprising administering to the patient a composition comprising PHY906.

In another embodiment, the present invention provides a method oftreating a bowel disorder, such as, for example, IBD and IBS, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a composition comprising an herbal preparation havingScutellaria, Glycyrrhiza, Ziziphus and Paeonia. In one preferredembodiment, the present invention provides a multiple symptoms(multi-symptom) treatment for the bowel disorder. For example, thepresent treatment can treat or relieve at least two or more symptoms ofthe bowel disorder. Exemplary symptoms include, but are not limited tovisceral pain, intestinal motility, inflammation, lower abdominal pain,bloating associated with alternation of bowel habits, abdominaldiscomfort relievable by defecation, fever, vomiting, acute diarrhea,positive stool culture, and combinations thereof.

As used herein, the term, “patient” includes mammal, preferably, human.By “therapeutically effective amount”, it is meant the amount of PHY906or other active agent(s) that, when administered to a patient fortreating a disease, is sufficient to effect such treatment for thedisease or relief of symptoms of the disease. The “therapeuticallyeffective amount” will vary depending on the age, weight, and severityof conditions of the patient to be treated.

In another embodiment, one or more additional active agents areco-administered to the patient for the treatment of the bowel disorder.The additional active agents can be any compound or biologics that haseffect of treating the bowel disorder. Examples of the additional agentincludes, but are not limited to the compound and biologics described inthe Background section of this application. By “co-administering”, it ismeant to administer PHY906 and the additional active agentsimultaneously or sequentially in such a manner to achieve a coordinatedor synergistic therapeutic effect.

Opioid receptors have long been known to be involved in pain perception,but they also play other important roles. In the gut, activation ofopioid receptors (by opiate drugs) in the gut wall results in decreasedtransit times⁽⁵⁸⁾. Circular muscle contractility plays a dominant rolein segmentation and peristalsis in the gut⁽⁵⁹⁾. Both and δ-opioidreceptors are involved in neurogenic circular muscle contractions; whenthese receptors are activated, such contractions are inhibited⁽⁶⁰⁾. Inone embodiment, PHY906, at a dose of 300 μg/ml, was shown tosignificantly inhibit δ-opioid receptors in vitro assays.

Common symptoms of IBS and IBD include visceral pain and/ordiscomfort⁽⁶¹⁾. Tachykinin NK-1 receptors are believed to play animportant role in mediating perception of such visceral pain⁽⁶²⁾. Inaddition, tachykinin NK-1 receptors are upregulated in the intestinallamina propria of mice with IBD and thus are involved in theinflammatory cascade that that triggers and maintains intestinal lesionsof IBD⁽⁶³⁾. As indicated by Table 3, four different batches of PHY906were shown to inhibit tachykinin NK-1 by using a radioligand bindingassay with human recombinant CHO cells.

TABLE 3 Inhibition of Tachykinin NK-1 by PHY906. IC₅₀ K_(i) Batch No.(μg/ml) (μg/ml) 906-6 263 144 906-7 247 135 906-8 486 265 906-9 430 235

Methods for the Tachykinin NK-1 Assay:

Human recombinant CHO cells were incubated in 20 mM HEPES buffer pH 7.4with 1 mM MnCl₂ and 0.01% bovine serum albumin and reacted with theligand 0.25 nM [³H] SR-140333 according to the method of Patacchini andMaggi⁽⁷⁰⁾. The non-specific ligand was 2 μM L-703606. IC 50 values weredetermined by a non-linear, least squares regression analysis using DataAnalysis Toolbox™ MDL Information Systems, San Leandro, Calif.). K_(i)values were calculated according to the equation of Cheng andPrusoff⁽⁷¹⁾.

In one embodiment, the present invention provides a method of inhibitinga δ-opioid receptor and/or a tachykinin NK-1 receptor by contacting theδ-opioid and tachykinin NK-1 receptors with a composition comprisingPHY906. The δ-opioid receptor and/or a tachykinin NK-1 receptor can bepresent in a cell, tissue, or organism. In another embodiment, thepresent invention provides a method of treating a disease or conditionassociated with a disregulated δ-opioid receptor or tachykinin NK-1receptor comprising administering to a patient in need thereof atherapeutically effective amount of a composition comprising PHY906.

Dysregulated cytokine production and signaling mechanisms by epithelialcells, mucosal lymphocytes, and macrophages in the gut have beenimplicated in the pathogenesis of both Crohn's and UC⁽⁶⁴⁾. In models ofCrohn's disease, the production of large amounts of cytokines such asinterferon-'γ (IFN-γ) and tumor necrosis factor (TNF), whose promotersare regulated by the transcription factor nuclear factor KB (NF-κB), isa major feature of the inflammation (65.66) Thus, downregulation ofNF-κB activity appears to be a potential key event in the control ofchronic intestinal inflammation⁽⁶⁷⁾. Inhibition of NF-κB activity hasbeen suggested as a major component of the anti-inflammatory activity ofglucocorticoids used to treat chronic intestinal inflammation^((68,69)).As shown in FIG. 3, PHY906 has inhibitory activity against bothintrinsic and TNF-activated NF-κB; this implies that PHY906 also hasanti-inflammatory activity and may be useful as a treatment for thechronic intestinal inflammation that characterizes IBD.

In one embodiment, the present invention provides a method of inhibitinga nuclear factor-kappa B (NF-κB) by contacting the NF-κB with acomposition comprising PHY906. The NF-κB can be present in a cell,tissue, or organism. In another embodiment, the present inventionprovides a method of treating a disease or condition associated with adisregulated NF-κB comprising administering to a patient in need thereofa therapeutically effective amount of a composition comprising PHY906.

While the present invention has been particularly shown and describedwith respect to preferred embodiments thereof, it will be understood bythose skilled in the art that the foregoing and other changes in formsand details may be made without departing from the spirit and scope ofthe invention. It is therefore intended that the present invention notbe limited to the exact forms and details described and illustrated butfall within the scope of the appended claims.

Furthermore, all publications cited herein are incorporated by referencein their entirety to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference.

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1. A method of treating a bowel disorder comprising administering to apatient in need thereof a therapeutically effective amount of acomposition comprising an herbal preparation having Scutellaria,Glycyrrhiza, Ziziphus and Paeonia.
 2. The method of claim 1, which treatmultiple symptoms of the bowel disorder.
 3. The method of claim 2,wherein the multiple symptoms comprises two or more symptoms selectedfrom the group consisting of visceral pain, intestinal motility,inflammation, lower abdominal pain, bloating associated with alternationof bowel habits, abdominal discomfort relievable by defecation, fever,vomiting, acute diarrhea, positive stool culture, and combinationsthereof.
 4. The method of claim 1, wherein the bowel disorder isinflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). 5.The method of claim 4, wherein the inflammatory bowel disease comprisesa condition selected from the group consisting of Crohn's disease,ulcerative colitis (UC), collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behçet's syndrome, infectivecolitis, indeterminate colitis, and combinations thereof.
 6. The methodof claim 4, wherein the irritable bowel syndrome comprises a conditionselected from the group consisting of diarrhea-predominant IBS,constipation-predominant IBS, alternating stool pattern IBS,post-infective IBS, and combinations thereof.
 7. The method of claim 1,further comprising co-administering to the patient in need thereof atherapeutically effective amount of at least one additional activeagent.
 8. The method of claim 7, wherein the additional active agent isselected from the group consisting of an aminosalicylate, acorticosteroid, an immunomodulator, an antibiotic, a biologic, andcombinations thereof.
 9. The method of claim 7, wherein the additionalactive agent is selected from the group consisting of a stool softener,a laxative, an antidiarrheal, an opiod or opiod analog, a tricyclic, aselective serotonin reuptake inhibitor, a probiotic, and combinationsthereof.
 10. The method of claim 1, further comprising acupuncture orsurgery.
 11. A method of inhibiting a δ-opioid receptor or a tachykininNK-1 receptor by contacting the δ-opioid and tachykinin NK-1 receptorswith a composition comprising an herbal preparation having Scutellaria,Glycyrrhiza, Ziziphus and Paeonia.
 12. The method of claim 11, whichcomprises inhibiting both a δ-opioid receptor and a tachykinin NK-1receptor.
 13. A method of treating a disease or condition associatedwith a disregulated δ-opioid receptor or tachykinin NK-1 receptorcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a composition comprising an herbal preparationhaving Scutellaria, Glycyrrhiza, Ziziphus and Paeonia.
 14. A method ofinhibiting a nuclear factor-kappa B (NF-κB) by contacting the NF-κB witha composition comprising an herbal preparation having Scutellaria,Glycyrrhiza, Ziziphus and Paeonia.
 15. The method of claim 14, whereinthe NF-κB is an intrinsic or activated form of NF-κB.
 16. A method oftreating a disease or condition associated with a disregulated NF-κBcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a composition comprising an herbal preparationhaving Scutellaria, Glycyrrhiza, Ziziphus and Paeonia.
 17. The method ofclaim 1, wherein the herbal preparation consists essentially ofScutellaria, Glycyrrhiza, Ziziphus and Paeonia.
 18. The method of claim11, wherein the herbal preparation consists essentially of Scutellaria,Glycyrrhiza, Ziziphus and Paeonia.
 19. The method of claim 13, whereinthe herbal preparation consists essentially of Scutellaria, Glycyrrhiza,Ziziphus and Paeonia.
 20. The method of claim 16, wherein the herbalpreparation consists essentially of Scutellaria, Glycyrrhiza, Ziziphusand Paeonia.